Methods of producing molindone and its salts

ABSTRACT

The present invention is directed towards novel methods of synthesis of molindone, synthesis of the intermediates of molindone, and high-purity compositions of molindone. In particular, the invention relates to the methods of synthesis of molindone through the Mannich reaction.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application Ser.No. 61/701,007 titled “METHODS OF PRODUCING MOLINDONE AND ITS SALTS,”filed on Sep. 14, 2012, which is incorporated herein, in its entirety,by this reference.

FIELD

Described herein are methods for improved production of activepharmaceutical ingredients (“APIs”) such as molindone, including methodshaving increased yields and producing decreased amounts of impurities.This disclosure further describes and characterizes salts of APIs suchas molindone hydrochloride, including novel polymorphs thereof.

BACKGROUND

Molindone is3-Ethyl-6,7-dihydro-2-methyl-5-(morpholinomethyl)indol-4(5H)-one (CAS#7416-34-4). The chemical formula of molindone is represented below:

Molindone is a weak base, exhibiting greater solubility in acidic toslightly acidic media than in neutral to slightly alkaline pH values(i.e., the physiologic pH range of the gastro intestinal tract). As aweakly basic drug, molindone is typically used in formulations in theform of a salt. Various prior art methods of manufacturing molindone,such as disclosed in U.S. Pat. No. 3,491,093 and U.S. Pat. No.3,646,042, are known. However, the prior art methods may result in adrug product that does not meet the modern purity requirements. Thus,what are needed in the art are methods for producing molindone whilereducing or eliminating the formation of certain impurities.

SUMMARY OF THE INVENTION

Provided herein are new and improved methods of manufacture of molindoneand its various salts, as well as molindone-related compounds, such asnovel intermediates. In particular, the methods herein provide asubstantially pure API of molindone salts, such as hydrochloride, whileavoiding undesirable impurities. The methods further provide forsynthesizing, separating, identifying, and characterizing novelpolymorphs of molindone. Further provided are methods of identificationand characterization and methods for synthesis of novel intermediates ofmolindone, as well as methods for synthesis of exemplary metabolites andprecursors of metabolites of molindone.

In an exemplary embodiment, the invention provides a substantially purecomposition suitable for use as an active pharmaceutical ingredient, thecomposition consisting essentially of molindone or a pharmaceuticallyacceptable salt thereof and comprising less than about 1.5 μg of anygenotoxic impurity per expected maximum human daily dose. In anotherexemplary embodiment, the composition comprises less than 0.5 μg of anygenotoxic impurity per expected maximum human daily dose.

In another embodiment, the invention provides a method of manufacturingmolindone through the reaction of2-methyl-3-ethyl-4-oxo-4,5,6,7-tetrahydroindole (SUMO-2) withbismorpholinomethane.

In yet another embodiment,2-methyl-3-ethyl-4-oxo-4,5,6,7-tetrahydroindole (SUMO-2) is produced byreacting 2,3-pentanedione-2-oxime and 1,3-cyclohexanedione.

In another embodiment, SUMO-2 is produced by reacting2-amino-pentan-3-one with 1,3-cyclohexanedione. In a further embodiment,2-amino-pentan-3-one is generated by reducing 2,3-pentanedione-2-oxime.

In a further embodiment, 2,3-pentanedione-2-oxime (SUMO-1) is producedthrough the reaction of 2,3-pentanedione with hydroxylaminehydrochloride.

In a specific embodiment, the invention provides a method ofmanufacturing molindone through a 3-step process, wherein in the 1ststep 2,3-pentadione is reacted with hydroxylamine hydrochloride toproduce 2,3-pentanedione-2-oxime (SUMO-1); in the 2nd step2,3-pentanedione-2-oxime and 1,3-cyclohexanedione are reacted to produce2-methyl-3-ethyl-4-oxo-4,5,6,7-tetrahydroindole (SUMO-2); and in the 3rdstep 2-methyl-3-ethyl-4-oxo-4,5,6,7-tetrahydroindole reacts withbismorpholinomethane to produce molindone (SUMO-3).

In yet another embodiment, the invention provides a method ofmanufacturing of a molindone salt by producing molindone base andreacting it with an acid.

In a further embodiment, various polymorphic forms of a molindone saltare prepared.

In yet a further embodiment, the invention provides a method ofmanufacturing molindone through a 5-step process, wherein in the 1ststep 2,3-pentanedione is reacted with hydroxylamine hydrochloride toproduce 2,3-pentanedione-2-oxime (SUMO-1); in the 2nd step2,3-pentanedione-2-oxime and 1,3-cyclohexanedione are reacted to produce2-methyl-3-ethyl-4-oxo-4,5,6,7-tetrahydroindole (SUMO-2); in the 3rdstep 2-methyl-3-ethyl-4-oxo-4,5,6,7-tetrahydroindole reacts withbismorpholinomethane to produce molindone (SUMO-3); in the 4th stepmolindone is converted into a molindone salt; and in the 5th step themolindone salt is purified/recrystallized, and, optionally, variouspolymorphic forms of molindone salt are prepared.

Further, the invention provides a method of manufacturing of themolindone-related compounds.

The present invention relates to a process for preparing a compoundSUMO-3, which includes the step of reacting (SUMO-2) withbismorpholinomethane. In one aspect of the present invention, theprocess includes the steps of removing methylene SUMO-2 by filtrationunder acidic conditions, adsorbing oligomeric compounds on charcoal, andfiltering and crystallizing SUMO-3 free base from a solvent. Withoutlimitation, the solvent can be selected from ethanol, methanol,isopropanol, butanol, acetone, ether, methyl t-butyl ether,nitromethane, ethyl acetate, toluene or combinations thereof. In oneembodiment, either of the processes as set forth above further includesa step of formation and crystallization of a salt of SUMO-3. Withoutlimitation, the salt can be molindone hydrochloride, molindone sulfate,molindone phosphate, molindone monohydrogenphosphate, molindonedihydrogenphosphate, molindone bromide, molindone iodide, molindoneacetate, molindone propionate, molindone decanoate, molindone caprylate,molindone formate, molindone oxalate, molindone malonate, molindonesuccinate, molindone fumarate, molindone maleate, molindone citrate,molindone lactate, molindone tartrate, molindone methanesulfonate, ormolindone mandelate. In another embodiment of any of the processes setforth herein, the amount of the residual isomer-SUMO-3 is less than0.2%.

In another embodiment of any of the processes set forth herein, thecompound SUMO-2 is prepared by reacting SUMO-1 with1,3-cyclohexanedione. In a further embodiment, the compound SUMO-2 isprepared by reacting SUMO-1 with 1,3-cyclohexanedione in the presence ofa catalyst. Exemplary catalysts include palladium on carbon (Pd/C) orRaney nickel.

In yet another embodiment of the present invention, the compound SUMO-2is prepared by reacting SUMO-1 with 1,3-cyclohexanedione in the presenceof zinc (Zn) in acetic acid. The Zn can be present in the form of apowder. In a further exemplary embodiment, the powder can have aparticle size of from about 2 microns to about 50 microns. In someembodiments, the SUMO-1 can be subjected to hydrogenation conditionsprior to the addition of 1,3-cyclohexanedione. In a further exemplaryembodiment, hydrogenation conditions include the use of a hydrogenationagent such as Zn/HOAC or a catalyst such as Pd/C or Raney nickel.

The process in accordance with embodiments of the present invention asset forth herein, may be initiated at a first temperature of from about15° C. to about 40° C. In one embodiment, the reaction temperature ofthe process may be further raised to a second temperature of from about80° C. to about 110° C.

In another aspect of the present invention, compound SUMO-1 is preparedby reacting 2,3-pentadione with hydroxylamine hydrochloride in thepresence of a base. Without limitation, the base can be LiOH, NaOH, KOH,Li₂CO₃, K₂CO₃, Na₂CO₃, NaHCO₃, or combinations thereof. In at least oneembodiment, the preparation of SUMO-1 is carried out at a pH of from 8to 9 to optimize regioselectivity.

In at least one embodiment, preparation of SUMO-1 can be carried out insuch a way that the ratio of SUMO-1/SUMO-1 isomer is at least 5:1.

Another aspect of the present invention relates to a substantially purecomposition including molindone or pharmaceutically acceptable saltsthereof, wherein the composition includes less than 1.5 μg of anygenotoxic impurity per expected maximum human daily dose.

There have thus been outlined, rather broadly, exemplary features of theinvention in order that the detailed description thereof that followsmay be better understood, and in order that the present contribution tothe art may be better appreciated. There are, of course, additionalfeatures of the invention that will be described further hereinafter.

In this respect, before explaining at least one embodiment of theinvention in detail, it is to be understood that the invention is notlimited in its application to the details of construction and to thearrangements of the components set forth in the following description orillustrated in the drawings. The invention is capable of otherembodiments and of being practiced and carried out in various ways.Also, it is to be understood that the phraseology and terminologyemployed herein are for the purpose of description and should not beregarded as limiting.

As such, those skilled in the art will appreciate that the conceptionupon which this disclosure is based may readily be utilized as a basisfor the designing of other structures, methods and systems for carryingout the several purposes of the present invention. It is important,therefore, that equivalent constructions insofar as they do not departfrom the spirit and scope of the present invention, are included in thepresent invention.

For a better understanding of the invention, its operating advantagesand the specific objects attained by its uses, reference should be hadto the accompanying drawings and descriptive matter which illustratepreferred embodiments of the invention.

DETAILED DESCRIPTION

As used above and throughout the description of the invention, thefollowing terms, unless otherwise indicated, shall be defined asfollows:

The term “equivalent” or “eq.” refers to the molar equivalent of thesubject compound.

The term “neat” means that the subject acid or base is undiluted with asolvent.

The term “basifying agent” means any compound which, via its presence ina composition, increases the pH of this composition by at least 0.05 pHunit, such as at least 0.1 pH unit.

Provided herein are new and improved methods of manufacture ofsubstantially pure compositions of molindone and pharmaceuticallyacceptable salts and polymorphs thereof with improved control ofimpurities to thereby provide materials suitable for pharmaceuticalapplications.

For the sake of convenience and without putting any limitations thereof,the methods of manufacture of molindone have been separated into severalindependent steps, each independent step being disclosed herein in amultiplicity of non-limiting and independent embodiments. Theseindependent steps comprise steps 1-3 and optional steps 4 and 5, whereinin the 1st step 2,3-pentadione is reacted with hydroxylaminehydrochloride to produce 2,3-pentanedione-2-oxime (SUMO-1); in the 2ndstep 2,3-pentanedione-2-oxime and 1,3-cyclohexanedione are reacted toproduce 2-methyl-3-ethyl-4-oxo-4,5,6,7-tetrahydroindole (SUMO-2); and inthe 3rd step 2-methyl-3-ethyl-4-oxo-4,5,6,7-tetrahydroindole reacts withbismorpholinomethane to produce molindone (SUMO-3). In the 4th stepmolindone is converted into a molindone salt; and in the 5th step themolindone salt is purified/recrystallized, and various polymorphic formsof the molindone salt are prepared.

The above-mentioned steps will be considered below in more details.

SUMO-3 Preparation Step

It was unexpectedly discovered that molindone (SUMO-3) may be preparedthrough the reaction of SUMO-2 with a Mannich reagent.

In one embodiment, the Mannich reagent used to prepare SUMO-3 isbismorpholinomethane.

The synthesis proceeds according to the Reaction 1:

Reaction 1:

The source of bismorpholinomethane useful for Reaction 1 is not limited.Bismorpholinomethane of sufficient purity may be acquired from acommercial source, or may be synthesized in situ. In one specificembodiment bismorpholinomethane is synthesized in situ according to theReaction 2:

Reaction 2:

The Mannich reagent (e.g., bismorpholinomethane) is used for thereaction in the amounts of from 1 eq to 4 eq. In one embodiment, theamount of the Mannich reagent (e.g., bismorpholinomethane) varies from 1eq to 2 eq. In another embodiment, the amount is between 2 eq and 4 eq.

The Reaction 1 is advantageously conducted in the presence of an acid.Representative acids may be selected from hydrogen chloride, aceticacid, formic acid, sulfuric acid, nitric acid, phosphoric acid,trifluoroacetic acid, and combinations thereof; and may be used in awide range of amounts, starting from 1 eq to up to a neat media to forma solution of the reaction mixture in the neat acid.

Further, a solvent may be added to the reaction mixture. The solvent maybe selected from methanol, ethanol, propanol, isopropanol, butanol,pentanol, ethylene glycol, ethoxyethanol, methoxyethanol, 1,4-dioxane,toluene, xylene, tetrahydrofuran, dichloromethane, benzene, andcombinations thereof.

Elevated temperature is used to facilitate the reaction. In at least oneembodiment, the reaction is conducted at the temperature of from 40° C.to 110° C. In alternative embodiments, the reaction is conducted at thetemperature of from 50° C. to 90° C.

The addition sequence, the ratio of the reagents, and the reactionconditions for Reaction 1 may be controlled to obtain maximum yield,improve the purity of the product or to control the side reactions thatlead to the formation of impurities.

In one embodiment, the reaction is conducted at a constant temperatureof from 60° C. to 110° C. In alternative embodiments, the reaction isconducted at a constant temperature of from 70° C. to 100° C.

In another embodiment, the reaction is initiated at the lower end of thetemperature range, and then the temperature is raised during thereaction. For example, the temperature may be raised to 65° C.-100° C.during the reaction.

In a further embodiment, the whole amount of the Mannich reagent (e.g.,bismorpholinomethane) is pre-charged at the initiation of the reaction.

In yet another embodiment, the Mannich reagent is added in a stepwisemanner with the initial amount charged at the start of the reaction,followed by the additional amount(s) added after some period of time.The timing of the second and further additions of the Mannich reagentmay vary but is typically selected from the period of time of between 1hour and 4 hours. The initial amount of the reagent constitutes from 50%to 90% of the total amount of the reagent; or from 60% to 80%. In someembodiments of the present invention, a Mannich reagent is added in acontinuous manner over a period of time. Exemplary time periods forcontinuous addition of a Mannich reagent include from about 1 hour toabout 4 hours.

In an additional embodiment for producing molindone with fewerimpurities, the reaction is advantageously initiated at the lower end ofthe temperature range with the initial amount(s) of the Mannich reagent(e.g., bismorpholinomethane), and followed by temperature increase andthe addition of the reagent as described in the previous embodiment.

The product of Reaction 1 is further purified. In one embodiment, theacidic solution containing the products of Reaction 1 is treated withwater to dissolve the molindone followed by filtration. Additional acidmay be added to increase the solubility of the molindone free base inthe aqueous phase. Additional acid in this embodiment can be selectedfrom hydrogen chloride (HCL), sulfuric acid (H₂SO₄), nitric acid (HNO₃),or phosphoric acid (H₃PO₄).

Upon completion of the Reaction 1, the aqueous acidic solutioncontaining the reaction products is treated with a base to obtain a pHof more than 7 to precipitate molindone (SUMO-3) free base. The basesused for molindone base precipitation may be selected from ammonia,carbonates, bicarbonates, hydroxides, and combinations thereof. The basemay be used in the form of a solution or in neat form. In a specificembodiment, an adsorbent can be additionally used during the basetreatment step to facilitate the filtration of the molindone precipitateand to remove impurities. The adsorbent may be selected from charcoal,zeolite, silicates, and celite.

The precipitated molindone base may be further dissolved andre-crystallized. Exemplary solvents useful for the re-crystallizationinclude ethanol, methanol, isopropanol, butanol, acetone, ether, methylt-butyl ether, nitromethane, ethyl acetate, toluene and combinationsthereof.

Potential impurities that could result from Reaction 1 include:

The novel reaction scheme of STEP 1 minimizes, or excludes, theformation of one or more of the above-listed impurities.

In an alternative embodiment, SUMO-3 may be prepared through the novelreaction process according to Reaction 3, wherein morpholine is used asa Mannich reagent. The Reaction 3 comprises steps 3a-3d and proceedsthrough the formation of two novel intermediates, formyl SUMO-2 andenamine of the formyl SUMO-2:

Reaction 3

SUMO-2 Preparation Step

While methods of preparation of SUMO-2 that are used to producemolindone according to the practice of the instant invention are knownin the art; it was unexpectedly discovered that SUMO-2 may beadvantageously produced through the reaction of SUMO-1 and1,3-cyclohexanedione under hydrogenating conditions in the presence of acatalyst. The reaction proceeds according to the following Reaction 4scheme:

Reaction 4:

It was further discovered that SUMO-2 can be advantageously producedwith fewer impurities by first producing an intermediate of thefollowing formula, followed by producing SUMO-2 in a stepwise manner.

In one embodiment, Reaction 4 is carried out as a single-stage reactionwithout accumulation of the intermediate. Beneficially, the reaction iscarried out in the presence of an acid. The acid may be an inorganic ororganic acid selected from hydrochloric acid, sulfuric acid, nitricacid, formic acid, acetic acid, trifluoroacetic acid, and combinationsthereof. In one variation, the acid is acetic acid.

The following possible by-products were identified in the reaction ofthis embodiment:

In another embodiment, Reaction 4 is carried out as a two-stagereaction, wherein the first stage of the reaction is a hydrogenationstage, and the second stage is a cyclization stage.

The hydrogenation stage is performed under low to moderate hydrogenpressure in the presence of a catalyst. An acid can be usedadvantageously in the hydrogenation stage to shorten the reaction time.The hydrogen pressure may be set between 1-5 bar. The acid useful forthe practice of this embodiment may be selected from HCl, sulfuric acid,acetic acid, trifluoroacetic acid, nitric acid and combinations thereof.In one specific example, the acid is acetic acid. In another example,the acid comprises acetic acid mixed with a solvent, such as ethylacetate, ethanol, methanol, benzene, toluene, xylene and combinationsthereof.

In the first variation of this embodiment, the reactants (SUMO-1 and1,3-cyclohexanedione) are pre-charged, and the hydrogenation stage iscarried out at the lower temperature in the presence of a catalyst. Inthis variation, the SUMO-2 intermediate is formed at lower temperature.The hydrogenation stage is then followed by the cyclization stagecarried out at higher temperature. The temperature for the hydrogenationstage may be from 15° C. to 40° C. In an alternative embodiment, thehydrogenation stage takes place at the temperature of 15° C.-25° C. Thetemperature for the cyclization stage is from 70° C. to 110° C., forexample, from 70° C. to 90° C., or from 90° C. to 100° C., or from 100°C. to 110° C.

In the second variation of the embodiment, the temperature protocolcorresponds to that of the first variation, but hydrogenation stageproceeds in the absence of 1,3-cyclohexanedione, which is charged laterat the high temperature cyclization phase. In this variation,2-amino-pentan-3-one is advantageously produced first. It wasunexpectedly discovered that the selectivity of Reaction 4 and the yieldand purity of SUMO-2 are improved by subjecting only SUMO-1 to thereduction conditions followed by the addition of 1,3-cyclohexanedione atthe later stage.

In one approach, the hydrogenation stage of Reaction 4 requires thepresence of a catalyst, such as Raney nickel catalyst, PtO₂ and Pdcatalyst.

In one embodiment of Reaction 4, the catalyst comprises Raney nickelcatalyst. The catalyst is used in this embodiment in the amounts of from0.01 g/g to 0.4 g/g, and more specifically, of from 0.05 g/g to 0.3 g/g.

In another embodiment of Reaction 4, the catalyst comprises Pd/Ccatalyst.

The catalyst is used in this embodiment in the amounts of from 0.01 g/gto 0.2 g/g, and more specifically, of from 0.05 g/g to 0.15 g/g.

Optionally, the used catalyst is removed from the reaction mixture afterthe hydrogenation step to prevent the formation of by-products.

Alternatively, the hydrogen necessary for the hydrogenation stage ofReaction 4 may be generated in situ by the addition of zinc powder inthe presence of acetic acid. In this case, the reaction may be carriedout with all reactants being charged at the beginning at lowertemperature followed by temperature increasing protocol; or with SUMO-1,zinc and the acid charged at the reduction stage, and withcyclohexanedione charged only at the cyclization stage, with or withouttemperature increasing protocol. Optionally, the residual zinc and zincacetate are filtered out after the hydrogenation. The particle size forthe zinc powder is in the range of from 2μ to 50μ. In an alternativeembodiment, the particle size for the zinc powder is in the range offrom 5μ to 20μ.

In one additional embodiment, SUMO-2 can be advantageously produced withfewer impurities by reacting 1,3-cyclohexanedione with2-amino-pentan-3-one of the following structure, which can be obtainedby reducing 2,3-pentanedione-2-oxime (SUMO-1),

By way of a non-limiting example, 2-amino-pentan-3-one can be obtainedby reducing 2,3-pentanedione-2-oxime (SUMO-1).

In order to remove impurities and undesired isomers, the product of theReaction 4, SUMO-2, is optionally subjected to at least onere-crystallization cycle.

The novel reaction schemes for the preparation of SUMO-2 minimize, orpreclude, the formation of one or more of the above-listed impurities.

SUMO-1 Preparation Step

Methods of preparation of SUMO-1 used for the preparation of SUMO-2 areknown in the art. SUMO-1 may be prepared, for example, through thereaction of 2,3-pentanedione with hydroxylamine hydrochloride in thepresence of a base (Reaction 5).

Reaction 5:

Generally, regioselectivity of the reaction of 2,3-pentanedione withhydroxylamine to SUMO-1 is not high, resulting in the formation of theSUMO-1 isomer 2,3-pentanedione-3-oxime and 2,3-pentanedione-2,3-dioxime,along with the desired product 2,3-pentanedione-2-oxime SUMO-1.

It was unexpectedly discovered that the regioselectivity of thisreaction can be optimized through the careful control of reactionconditions, such as the nature and amount of the basifying agent, pH,solvents, temperature and a dosing sequence.

The process of Reaction 5 may be carried out at pH values ranging from4.5 to 9.5.

In one embodiment, Reaction 5 takes place at pH values ranging from 4.5to 8. In another embodiment, the reaction takes place at pH values inthe range of from 8 to 9.5.

The base, useful for establishing the necessary pH, may be selected fromlithium hydroxide (LiOH), sodium hydroxide (NaOH), potassium hydroxide(KOH), lithium carbonate (Li₂CO₃), potassium carbonate (K₂CO₃), sodiumcarbonate (Na₂CO₃), and combinations thereof. The base may be employedin the amounts of from 1.0-3.0 eq, for example, in the amount of1.05-1.5 eq or 1.05-2.0 eq.

In one embodiment of SUMO-1 preparation, the base is selected from NaOH,KOH and combinations thereof. In another embodiment, the base isselected from Li₂CO₃, K₂CO₃, Na₂CO₃, and combinations thereof.

In yet another embodiment, the base is Na₂CO₃, which may be used in theamounts of from 1 to 3 equivalents. In one variation of this embodiment,sodium carbonate was used in the amount of about 1.0 equivalent. In afurther variation of this embodiment, sodium carbonate was used in theamounts of 1.1 equivalents. In yet another variation, sodium carbonatewas used in the amount of 1.2 equivalents.

As it was discovered that the lower temperature of the reaction leads tobetter selectivity, Reaction 5 advantageously takes place at atemperature of from 5° C. to 20° C. In one embodiment, the reactiontakes place at a temperature of from 5° C. to 0° C. In anotherembodiment, the temperature is from 0° C. to −15° C. In yet anotherembodiment, the temperature is set to be from −5° C. to −10° C.

Further, an addition of an anti-freezing agent to lower the freezingpoint of the solution is beneficial for the reaction. The anti-freezingagent can be selected from the alkaline and alkaline earth metalhalides, such as sodium chloride (NaCl), potassium chloride (KCl),calcium chloride (CaCl₂), magnesium chloride (MgCl₂), and the like.

The solvents useful for the reaction of Reaction 5 are selected from thegroup consisting of water, methyl tertiary butyl ether (MTBE), methanol,ethanol, isopropanol, tetrahydrofuran (THF), acetonitrile, pyridine,ethyl ether, acetic acid and combinations thereof. The followingsolvents may be additionally added to provide anti-freezing properties:glycerol, ethylene glycol, propylene glycol, diethylene glycol andcombinations thereof.

A high yield of SUMO-1, above 90%, can be obtained through realizing theabove-described embodiments of Reaction 5, with reduced amounts ofimpurities generated in the product.

The following compounds were identified as potential by-productsresulting from Reaction 5:

The novel reaction scheme of this step minimizes, or precludes, theformation of one or more of the above-listed impurities.

In alternative embodiments, the ratio of SUMO-1 to SUMO-1 isomer wasdetermined to be above 5, above 6, or above 6.5.

In one embodiment of SUMO-1 preparation, the levels of the2,3-pentadione-2,3-dioxime impurities are not exceeding 0.2%. Inalternative embodiments, the levels of the 2,3-pentadione-2,3-dioximeimpurities are not exceeding 0.1%.

Purified molindone (SUMO-3) free base produced according to the practiceof the instant invention may be converted into a molindone salt, such aschloride, sulfate, phosphate, monohydrogenphosphate,dihydrogenphosphate, bromide, iodide, acetate, propionate, decanoate,caprylate, formate, oxalate, malonate, succinate, fumarate, maleate,citrate, lactate, tartrate, methanesulfonate, mandelate and the like.The salts may be prepared through the reaction of molindone base withthe acid in a warm alcoholic solution, followed by cooling. The solventuseful for the salt formation may be selected from MTBE, methanol,ethanol, isopropanol, THF, acetonitrile and combinations thereof, whichcan be combined with ethyl acetate, hexane, heptane, benzene, toluene,cyclohexane, or water. In at least one embodiment, the temperature ofthe alcoholic solution for crystallization is in the range of from −20°C. to 25° C.

In one specific, but non-limiting, embodiment the salt is molindone HCl.

The invention further provides a substantially pure compositionconsisting essentially of molindone or pharmaceutically acceptable saltsthereof. In varying embodiments, the term “substantially pure” refers tocompositions containing essentially only the active pharmaceuticalingredient and less than about 1.5 μg (or less than about 0.5 μg) of anygenotoxic impurity per expected maximum human daily dose, and they aretherefore suitable for use in the preparation of pharmaceutical dosageforms intended for human consumption. Further, in varying embodiments,the term “substantially pure” refers to compositions containing at leastabout 98% (or alternatively at least about 99%, or at least about 99.5%)by weight of the active pharmaceutical ingredient. Even further, theterm “substantially pure” refers to compositions containing less thanabout 0.1% of any single unknown impurity. In this context, an“impurity” refers to reaction side-products or reaction intermediates orresidual reagents or undesirable products thereof, which may remain inthe active pharmaceutical ingredient after synthesis. In varyingembodiments, the “substantially pure” compositions referred to hereincontain only the inventive active pharmaceutical ingredient as theprincipal or the sole physiologically or pharmacologically activecomponent.

As used herein, the term “genotoxic” refers to compounds or substancesthat are suspected to, or have demonstrated to, induce geneticmutations, chromosomal breaks and/or chromosomal rearrangements.

By way of example, a “substantially pure” composition of molindone (or apharmaceutically acceptable salt thereof) contains less than about 1.5μg, less than about 1.0 μg, and less than about 0.5 μg of any genotoxicimpurity per maximum daily molindone dose in humans.

In another embodiment, the invention provides novel compounds accordingto the following formulas:

In the additional embodiment of the invention, the new and improvedmethods of manufacture of molindone disclosed above can be used toprepare molindone-related compounds by using corresponding SUMO-1analogs and bismorpholinomethane analogs. The preparation is exemplifiedin reactions 6, 7, 8 and 9, wherein R1, R2, R3, R4, and R5 are selectedfrom —H, —OH, alkoxy, alkyl, or substituted alkyl groups.

Reaction 6:

Reaction 7:

Reaction 8:

Reaction 9:

Examples of the molindone analogs that can be prepared by reactions 6,7, 8 and 9 include, but are not limited to:

Further, hydroxymethyl SUMO-2 of the formula below,

can be prepared by reacting SUMO-2 with formaldehyde, and used with thebismorpholinomethane analogs in combination with the methods disclosedherein to produce molindone analogs with the following formula:

EXAMPLES

The invention now being generally described, it will be more readilyunderstood by reference to the following examples which are includedmerely for purposes of illustration of certain aspects and embodimentsof the present invention, and are not intended to limit the invention.

Examples for SUMO-1 Preparation Step Example 1 Preparation of SUMO-1

2,3-pentanedione and hydroxylamine hydrochloride were dissolvedseparately in water/EtOH (3/1; w/w %). Then the solution ofhydroxylamine hydrochloride was added to the solution of2,3-pentanedione at predetermined pH and low or room temperature. ThepH-value of the reaction-mixture was adjusted with 1N NaOH. The finalconcentration of 2,3-pentanedione in the reaction-mixture was ˜3.5 w %.After the reaction, the solution was extracted with MTBE.

The same procedure was repeated at various temperatures and pH values.The results are presented in Tables 1 and 2.

TABLE 1 Effect of pH on SUMO-1 Yield (T = 3° C.) Experiment # pH Yield(%)* PER-3131-1 4.5 57.9 PER-3132-1 6.5 75.7 PER-3130-1 8.5 81.1 *Asarea % in HPLC

TABLE 2 Effect of Temperature on SUMO-1 Yield (pH = 8.5) Experiment #Temperature (° C.) Yield (%)* PER-3129-1 Room 68.2% temperaturePER-3130-1  3° C. 81.1% PER-3137 −5° C. 82.2% *As area % in HPLC

Example 2 Preparation of SUMO-1

An aqueous solution of sodium carbonate (ca. 12% w/w) was cooled to 0°C., followed by dosing of an aqueous solution of hydroxylaminehydrochloride (ca. 20% w/w). Then an ethanolic solution of pentandione(50 w %) was dosed at 0° C. over 2 hours.

After aging for 1 hour at 0° C., the reaction mixture was warmed to roomtemperature and MTBE was added to dissolve the partially precipitatedpartially oily product (6 g MTBE/g pentandione). The aqueous layer wasdiscarded, the organic layer was concentrated at reduced pressure (40°C., 300 to 50 mbar), the resulting oil solidified upon standing at roomtemperature.

To facilitate the transition to Step 2, a solvent switch may beperformed from MTBE/EtOH to the solvent used in the second step (aceticacid) instead of completely removing the solvent and letting the oilsolidify.

The same procedure was repeated with varying amounts of the base atvarious temperatures. The results are presented in Tables 3 and 4.

TABLE 3 Effect of Base Amount on SUMO-1/SUMO-1 Isomer Ratio Amount ofSUMO-1/Isomer Experiment # Na₂CO₃ (eq) pH Yield * Ratio Han-601 1.20 8.983.9 5 Han-602 1.05 8.1 82.4 5.4 Han-603 1.1 8.5 83.5 5.9 * As area % inHPLC

TABLE 4 Effect of Temperature on SUMO-1/Isomer Ratio (1.1 Eq. of Na₂CO₃)Temperature SUMO-1/Isomer Experiment # (° C.) Yield * Ratio Han-603 083.5 5.9 Han-606 −5 85.0 6.3 Han-607 −8 85.2 6.5 Han-609 −10 82.8 6.4 *As area % in HPLC

Examples for SUMO-2 Preparation Step Example 3 Preparation of SUMO-2 in1-Stage Reaction

1 eq. of SUMO-1 and 1 eq. of 1,3-cyclohexanedione were dissolved inacetic acid. Four catalysts (2 Pd/C and 2 Raney-nickel) were used on asmall scale at 25° C. to 40° C. and 1-5 bar hydrogen pressure. With all4 catalysts, SUMO-1 was eventually completely consumed; the reaction,however, was a little faster on the Pd/C catalysts than the Raney-nickelones. At the low temperature, an intermediate with the following formulawas formed,

characterized by a late eluting peak (9.6 min). When the reactiontemperature was raised to 100° C., the late eluting peak started todecrease and SUMO-2 increased.

Example 4 Preparation of SUMO-2 Intermediate Using Pd/C Catalyst

SUMO-1 (1 eq.) and 1,3-cyclohexanedione (1 eq.) were dissolved in ethylacetate/acetic acid (3:1) and 0.1 g/g Pd/C catalyst was added. Thereaction was carried out at 1 bar of hydrogen at 50° C., and theconversion to the intermediate worked smoothly.

Example 5 Preparation of SUMO-2 Using Pd/C Catalyst in a 2-StageReaction

SUMO-1 in acetic acid (˜10 w %) was charged into the autoclave, followedby 0.1 g/g Pd/C. The autoclave was pressurized to 3 bar with hydrogen.The reaction mixture was stirred at 25° C. until hydrogen consumptionindicated complete conversion (˜15 h). Then the catalyst was filteredoff and 1,3-cyclohexanedione (1.1 eq) in some acetic acid (˜50 w %) wasadded. The reaction mixture was heated to 110° C. jacket temperature(˜100° C.-105° C. internal) and stirred until GC shows completeconversion (˜5 h). Then the reaction mixture was cooled to 50° C. andpart of the acetic acid was removed under reduced pressure (to ca. 3 g/gSUMO-1). This solution was slowly added into 3 times the weight ofchilled (2° C.) water. After aging at 2° C. for 1 h, the product wasisolated by filtration, washed with water and dried at 40° C. in vacuoto yield 54% SUMO-2 crude with ˜11% isomer. SUMO-2 crude was suspendedin methanol/water=2/1 (v/v) (10 w %) at room temperature. Then thereaction mixture was heated to 75° C. jacket temperature, and a clearsolution was obtained somewhere between 60 and 70° C. internaltemperature. Then the reaction mixture was cooled to 0° C. within 2hours and the reaction mixture was aged at 0° C. for 1 hour. Then theproduct was isolated by filtration, washed with methanol/water and driedat 40° C. in vacuo to yield 76% SUMO-2 with ˜2% isomer from SUMO-2crude, or 41% yield overall.

Example 6 Preparation of SUMO-2 Using Ra Ni Catalyst in a 2-StageReaction

SUMO-1 in acetic acid (˜10%) was reacted with 1,3-cyclohexadione in thepresence of 0.3 g/g Raney nickel catalyst at 25° C. under 3 bar ofhydrogen. The catalyst was filtered off and the temperature wasincreased to 100° C. A 42.4% yield of SUMO-2 was obtained.

Example 7 Preparation of SUMO-2 Using Zn/HOAc

17.5 g (156.5 mmol) 1,3-cyclohexanedione and 16.8 g (144 mmol) SUMO-1(PER-3143-1) were dissolved in 156 g acetic acid at room temperature.20.5 g (313 mmol) powder Zn was added in small portions over a period of˜1 hour, and the mixture was stirred at reflux for 1 hour. Thesuspension was cooled down to room temperature. Then the suspension wasfiltered off via celite and the celite was washed with 40 g acetic acid.The yellow brown solution was concentrated in vacuum to 50 g solutionand then it was added over a period of 15 minutes to 150 g cold water(2° C.). A slightly brown solid was precipitated. The suspension wasfurther stirred for 1 hour at 2° C. and filtered off. The filter cakewas washed twice with 40 ml cold water. The slightly brown solid wasdried in vacuum at 40° C.:

-   Yield: 19.7 g (77%)

Example 8 Preparation of SUMO-2 Using Zn/HOAc in a 2-Stage Reaction

1,3-cyclohexanedione and SUMO-1 were dissolved at room temperature inacetic acid. Then powder Zn was added in small portions. The mixture wasthen stirred at reflux. Reaction mixture was worked up as described inExample 7.

SUMO-1 was dissolved at room temperature in acetic acid. Powder Zn wasadded in small portions. The mixture was then stirred at reflux. Zn wasthen removed by filtration. 1,3-cyclohexanedione was added. The reactionmixture was stirred at reflux. The reaction mixture was worked up asdescribed in Example 7.

Results:

SUMO-2 rrt = 0.74 rrt = 0.88 Rrt = 0.99 SUMO-2 isomer % area % area %area % area % area SUMO-2:SUMO-2 Entry count count count count countisomer ratio Hil-3194 80.3 0.73 0.62 0.11 18.0 4.7:1 Hil-3195 84.3 0.460.42 Not detected 14.7 5.7:1

Example 9 Purification of SUMO-2

-   -   1. SUMO-2 was prepared as disclosed in Example 5.

After the removal of the acetic acid, the reaction mixture was dividedinto four parts.

-   -   a. The warm solution of SUMO-2 in acetic acid was dosed slowly        into cold water.    -   b. The second part was crystallized similar to the        re-crystallization procedure by dissolving SUMO-2 in residual        acetic acid, methanol and water at 70° C. and slowly cooling to        2° C., improving the depletion of the undesired isomer.    -   c. In the third part, water was added into the cold solution of        SUMO-2 in residual acetic acid and methanol.    -   d. The fourth part finally was performed by adding cold water to        the ˜50° C. warm solution of SUMO-2 in residual acetic acid.

TABLE 5 Purification SUMO-2 Treat- Treat- Treat- Treat- ment (a) ment(b) ment (c) ment (d) Yield (%) 56 32.7 35.1 57.2 SUMO-2 (%) 83.1 95.193.8 82.5 SUMO-2 15.7 4.67 5.99 16.5 Isomer (%)

-   -   2. First recrystallization: 18 g of crude SUMO-2 from example 7        was dissolved in 162 g MeOH/water (2/1; v/v %) at 75° C. and the        solution was cooled down to 0° C. over a period of 2 h. The        suspension was stirred for 1 h at 0° C. and filtered off. The        filter cake was washed twice with 50 ml MeOH/water (2/1; v/v %)        and dried in vacuum at 40° C. Total yield: 12.8 g.    -   3. Second re-crystallization: 12.5 g of SUMO-2 obtained after        the first re-crystallization was dissolved in 120 g MeOH/water        (2/1; v/v %) at 75° C. and the solution was cooled down to 0° C.        over a period of 2 hours. The suspension was stirred for 1 hour        at 0° C. and filtered off. The filter cake was washed twice with        35 ml MeOH/water (2/1; v/v %) and dried in vacuum at 40° C.        Overall yield of 10.5 g (45%) was achieved.

Examples for SUMO-3 Preparation Step Example 10 Preparation ofN-hydroxymethyl SUMO-2

SUMO-2 is reacted with formaldehyde in the presence of aqueous acid (aq.HCl, aq. HOAc, or aq. H2SO4) to produce N-hydroxymethyl-SUMO-2 of thefollowing structure:

Example 11 Preparation of SUMO-3 by Reacting SUMO-2 withBismorpholinomethane

The reaction of bismorpholinomethane with SUMO-2 was conducted withdifferent solvents and acids: ethanol, ethanol/HCl and acetic acid, eachat elevated temperature. The neutral conditions in ethanol and withoutacid showed virtually no reaction after 2 hours. In ethanol withhydrochloric acid ˜10% area count of SUMO-3 was formed after 2 hours. Inacetic acid after 2 h, ˜50% area count of SUMO-3 was formed and ˜25%area count of SUMO-2 remained.

TABLE 7 The reaction of bismorpholinomethane with SUMO-2 under differentsolvents Amount of Reaction Mannich Experiment # Temp (° C.) Reactant(Eq) Solvent Hil-3238 80 1 EtOH Hil-3239 80 1 EtOH/HCl Hil-3240 80 1AcOH

Example 12 Preparation of SUMO-3 by Reacting SUMO-2 withBismorpholinomethane

-   -   a. SUMO-2 was dissolved in acetic acid and heated to 65° C.        Bismorpholinomethane (1.5 eq) was dosed over ˜30 minutes; the        progress of the reaction was followed by HPLC. After 3 hours,        the reaction temperature was increased to 80° C. After 3 hours        at 80° C., 9% area count of compound at rrt=0.82 was left, 44%        area count of SUMO-3 formed and 25% area count of SUMO-2 was        left (and <1% area count of methylene-SUMO-2). The reaction        mixture was stirred at 80° C. overnight and after 18 hours at        80° C., the following HPLC was observed: <1% area count of        compound at rrt=0.82, 59% area count of SUMO-3, 20% area count        of SUMO-2 and 7% area count of methylene-SUMO-2.    -   b. Incremental Addition of Bismorpholinomethane    -   2.0 eq of bismorpholinomethane was charged to SUMO-2 dissolved        in acetic acid at 80° C. directly. At this temperature, SUMO-3        already started to appear from the first HPLC in significant        amounts and the intermediate rrt=0.82 was formed only in smaller        amounts. After 3 hours, another 0.5 eq of bismorpholinomethane        was charged. After 20 hours, the reaction was stopped with ˜62%        area count of SUMO-3, <1% area count of compound at rrt=0.82,        ˜15% area count of SUMO-2 and ˜15% area count of        methylene-SUMO-2.    -   c. SUMO-2 was dissolved in acetic acid and heated to 50° C. The        reaction was pushed to 90% conversion, which was achieved by        starting out with 2.5 eq and charging another 0.5 eq of        bismorpholinomethane after a few hours. With less than 11%        SUMO-2 (and >80% of the intermediate rrt=0.82) left, the        temperature was increased to 80° C., and the reaction mixture        was stirred for 10 hours. Surprisingly, after 10 hours at 80° C.        the reaction mixture contained 59% SUMO-3, 3% rrt=0.82 and 20%        SUMO-2.    -   d. SUMO-2 was dissolved in acetic acid and heated to 50° C.    -   Bismorpholinomethane was charged at 50° C. (2 eq). After 2        hours, the temperature was raised to 80° C. After 2 hours aging        at 80° C., another 1 eq of bismorpholinomethane was added,        followed by 10 hours aging at 80° C. Only 11% of residual SUMO-2        remained; the yield of SUMO-3 was close to 60% area count.

TABLE 8 Preparation of SUMO-3 with Bismorpholinomethane: Temperature andCharging Conditions Initial Ramp Initial Amount Ramp Amount Temp Temp ofMannich of Mannich Experiment # ° C. ° C. Solvent Reagent (Eq) Reagent(Eq) Hil-3243 65 80 AcOH 1.5 n/a Hil-3245 80 n/a AcOH 2 0.5 Han-622 5080 AcOH 2.5 0.5 Hil-3250 50 80 AcOH 2 1

Example 13 Work-Up of SUMO-3 after the Reaction of SUMO-2 withBismorpholinomethane

To remove impurities, such as methylene-SUMO-2 and SUMO-2, most of theacetic acid was distilled off and water was added. Another acid such asHCl and H₂SO₄ can be used to adjust the pH of the aqueous solution.SUMO-3 remained in solution whereas the impurities crashed out as aslightly sticky solid and was filtered off. Then the reaction mixturewas warmed to 40° C., MTBE was added and the pH was adjusted to >7 withsodium hydroxide. Afterwards the phases were separated and the aqueouslayer was extracted a second time with MTBE. The MTBE phase wasconcentrated and SUMO-3 free base was crystallized upon cooling at 50.8%yield (89.8% purity).

Alternatively, after the filtration of the crashed-out impurities asdescribed above, the pH-adjustment of the acidic solution was performedas follows: charge the acidic solution, warm to 45° C., charge charcoal,charge MTBE, charge ethanol and then dose sodium hydroxide to liberatethe SUMO-3 free base. Charcoal was added to bind the semi-solidby-product and facilitate its removal by filtration and washedafterwards with MTBE/EtOH solvent. The combined MTBE/EtOH wasconcentrated to produce SUMO-3 free base crystals.

Example 14 SUMO-3 Free Base

SUMO-3 free base was crystallized from MTBE/EtOH mixture or from EtOH.45% overall yield was obtained with high purity (98%).

Example 15 Molindone Hydrochloride Formation

SUMO-3 free base was converted into the hydrochloride salt with HCl/EtOH(i-PrOH) and crystallized from ethanol or isopropanol. Molindone HCl wasobtained with high yield (95%) and high purity (99.5%).

What is claimed is:
 1. A process for preparing a compound SUMO-3comprising a step of reacting SUMO-2 with bismorpholinomethane.
 2. Theprocess of claim 1 further comprising at least one of the followingsteps: (a) removal of methylene SUMO-2 by filtration under acidicconditions; (b) adsorbing oligomeric compounds on charcoal; (c)filtering and crystallizing SUMO-3 free base from a solvent.
 3. Theprocess of claim 1 further comprising a step of formation andcrystallization of a salt of SUMO-3.
 4. The process of claim 3 whereinsaid salt is selected from the group consisting of molindonehydrochloride, molindone sulfate, molindone phosphate, molindonemonohydrogenphosphate, molindone dihydrogenphosphate, molindone bromide,molindone iodide, molindone acetate, molindone propionate, molindonedecanoate, molindone caprylate, molindone formate, molindone oxalate,molindone malonate, molindone succinate, molindone fumarate, molindonemaleate, molindone citrate, molindone lactate, molindone tartrate,molindone methanesulfonate, and molindone mandelate.
 5. The process ofclaim 1 wherein the compound SUMO-2 is prepared by reacting SUMO-1 with1,3-cyclohexanedione.
 6. The process of claim 5 wherein the compoundSUMO-2 is prepared by reacting SUMO-1 with 1,3-cyclohexanedione in thepresence of a hydrogenation catalyst.
 7. The process of claim 5 whereinthe compound SUMO-2 is prepared by reacting SUMO-1 with1,3-cyclohexanedione in the presence of Zn in acetic acid.
 8. Theprocess of claim 6 wherein said catalyst comprises Pd/C.
 9. The processof claim 6 wherein said catalyst comprises Raney nickel.
 10. The processof claim 5 wherein SUMO-1 is subjected to the hydrogenation conditionsprior to the addition of 1,3-cyclohexanedione.
 11. The process of claim10 wherein SUMO-1 is hydrogenated in the presence of Zn and an acid. 12.The process of claim 11 wherein Zn is removed prior to the addition of1,3-cyclohexanedione.
 13. The process of claim 10 wherein SUMO-1 ishydrogenated in the presence of a catalyst.
 14. The process of claim 13wherein the catalyst is removed prior to the addition of1,3-cyclohexanedione.
 15. The process of claim 13 wherein said catalystcomprises Pd/C.
 16. The process of claim 13 wherein said catalystcomprises Raney nickel.
 17. The process of claim 5 wherein the processis initiated at a first temperature of from 15° C. to 40° C.
 18. Theprocess of claim 17 wherein the temperature is raised during the processto a second temperature of from 80° C. to 110° C.
 19. The process ofclaim 5 wherein the compound SUMO-1 is prepared by reacting2,3-pentanedione with hydroxylamine hydrochloride in the presence of abase.
 20. The process of claim 19 wherein said base is selected from thegroup consisting of LiOH, NaOH, KOH, Li₂CO₃, K₂CO₃, Na₂CO₃, NaHCO₃ andcombinations thereof.
 21. The process of claim 19 wherein thepreparation of SUMO-1 is carried out at a pH of from 8 to 9 to optimizeregioselectivity.
 22. The process of claim 21 wherein the ratio ofSUMO-1/SUMO-1 isomer is at least 5:1.
 23. The process of claim 1 whereinthe amount of the residual isomer SUMO-3 is less than 0.2%.
 24. Theprocess of claim 2 where the solvent is selected from the groupconsisting of ethanol, methanol, isopropanol, butanol, acetone, ether,methyl t-butyl ether, nitromethane, ethyl acetate, and toluene.
 25. Theprocess of claim 1 wherein the reaction is conducted in the presence ofan acid.
 26. The process of claim 25 wherein said acid is selected fromthe group consisting of HCl, acetic acid, formic acid, sulfuric acid,nitric acid, phosphoric acid, and trifluoroacetic acid.
 27. A processfor preparing a compound SUMO-2 comprising a step of reacting SUMO-1with 1,3-cyclohexanedione.
 28. A process for preparing a compound SUMO-2by reacting 2-amino-pentan-3-one with 1,3-cyclohexanedione.
 29. Theprocess of claim 1 wherein the reaction is conducted in the presence ofa solvent.
 30. A substantially pure composition consisting essentiallyof molindone or pharmaceutically acceptable salts thereof, saidcomposition comprising less than 1.5 μg of any genotoxic impurity perexpected maximum human daily dose.
 31. The process of claim 7 whereinthe Zn is present in the form of a powder with a particle size of from2μ to 50μ.
 32. A process for preparing a compound SUMO-3 comprising thesteps of (a) forming formyl SUMO-2 by reacting SUMO-2 with ethylformate; (b) reacting formyl SUMO-2 with morpholine to form an enamineof formyl SUMO-2; (c) reducing the enamine to form molindone.